FR2999082A1 - Inhalable drug, useful for preventing or treating a neurological consequence relating to neonatal hypoxia ischemia, and to perinatal asphyxia in a new-born baby, comprises argon gas - Google Patents

Abstract

Inhalable drug comprises argon gas. ACTIVITY : Neuroprotective. MECHANISM OF ACTION : None given.

Description

The invention relates to the use of argon gas as an inhalable drug, used in combination with hypothermia, to treat or prevent any neurological consequence related to neonatal hypoxia of ischemic origin, due to asphyxia. perinatal.

Perinatal asphyxia is a lack of oxygen in the brain during delivery, at the time of birth, and immediately after birth. This disease affects 3 to 5 newborns per 1000 live births in developed countries. As recalled by R. Vannucci; Paediatrics 1999; 85: 961-9682, hypoxic-ischemic encephalopathy (EHI) brain injury results in 1 newborn per 1000 live births, and nearly 60% of newborns with EHI die, while 25% survivors develop a significant disability. As a result, perinatal asphyxia is a significant problem and one of the leading causes of neonatal mortality and significant disability among survivors.

Until recently, there was no effective treatment for EHI. Once the newborn was asphyxiated, it was impossible to prevent brain damage from occurring and this often led to the death of the newborn. Moderate cooling of the brain, that is, a temperature lowered to between 32 and 34 ° C, has been proposed as a means of preventing brain damage and mortality in neonates with asphyxia. For example, a meta-analysis showed that therapeutic hypothermia in term neonates with moderate to severe IHD leads to a reduction in the combined result of mortality or major neurodevelopmental abnormality in the long-term. the age of 18 months.

Hypothermia is defined by a body temperature lowered by a few degrees but above 30 ° C, and is maintained for less than 72 hours. These results are significantly and clinically important and are associated with an absolute 15% risk reduction, as recalled by Jacobs et al., Cochrane database of systemic reviews; 2007; Issue 4.

However, hypothermia alone is not sufficient and does not allow to hope to significantly reduce the EHI lesions related to perinatal asphyxia. In addition, it has been shown that certain deficiencies or failures affecting the brain can be treated with inhaled gases, such as xenon. Thus, EP-A-1158992 proposes to use inhaled xenon to fight against cerebral neuro-intoxications, particularly ischemic, which are characterized by cerebral dysfunction of one or more neurotransmission systems. In addition, the document EP-A-1651243 proposes using Xe / N20 mixtures inhaled for this purpose, whereas DE-A-19991033704 proposes liquid formulations containing dissolved xenon for treating hypoxia and hypoxia. cerebral ischemia. It has been shown that xenon can protect the brain in newborn animals in a state of neonatal asphyxia. Thus, the document by Chakkarapani et al. ; Ann. Neurol. 2010 Sep; 68-3: 330-41, showed that the combination of xenon and hypothermia had an additive effect, resulting in 75% of histological neuroprotection after 24 h of this combination. Similarly, EP-A-1670489 relates to a combination of xenon and hypothermia which increases neuroprotection in vitro after neonatal asphyxia.

Phillips et al., Eur. J. of Pharmacology, 2012, suggested that hypothermia would act particularly via N-methyl-D-aspartate receptors, just like xenon, which could explain the potential effect of xenon associated with hypothermia. However, there are no clinical trials where this combination xenon / hypothermia has been tested in neonates with HIE. This is due in particular to the complexity of combining the technique of hypothermia with a dedicated ventilation for a gas such as xenon whose administration requires a specific fan, allowing its recirculation in closed circuit. In addition, the cost and complexity of purification of xenon, which is an existing gas in very small proportions in the ambient air, is a brake to its use.

It follows that the non-existence, to date, of a therapeutic combination more effective than hypothermia alone does not allow to hope to significantly reduce the EHI lesions related to perinatal asphyxia. The problem is therefore to propose a treatment that can effectively treat newborns in order to significantly prevent EHI-induced brain damage in relation to perinatal asphyxia. This treatment should be more effective than hypothermia alone and should not pose the problems and disadvantages encountered with the combination xenon / hypothermia. The solution according to the present invention is an inhalable drug containing argon gas for use by inhalation in combination with hypothermia to prevent or treat a neurological consequence related to neonatal hypoxia of ischemic origin, following perinatal asphyxia. in a newborn baby. Depending on the case, the inhalable drug or gas composition of the invention may comprise one or more of the following features: the drug contains an effective amount of argon gas, i.e., at least 10% by volume argon, - the drug contains between 15 and 80% by volume of argon (% by volume). the drug contains at least 20% by volume of argon. the drug contains at least 30% by volume of argon. it contains less than 75% by volume of argon. - the newborn is less than 30 days old. the newborn is a mammal, preferably a human being. hypothermia is obtained by maintaining the body temperature of the neonate between 30 and 36 ° C, typically at least 32 ° C and at most 35 ° C. Between 32 ° and 35 ° C, we speak of moderate hypothermia. the body temperature of the neonate between 30 and 36 ° C. is maintained for a period of between 1 h and 72 h, preferably of at least 4 h. the drug contains exclusively argon, said argon being mixed with oxygen before it is inhaled by the newborn, preferably at least 21% by volume of oxygen. the gaseous composition forming the medicament further contains an additional compound selected from the group consisting of N 2 O, He, Ne, NO, CO and N 2. Argon is administered to the patient one or more times a day for an inhalation period of a few minutes to one or more hours. the gaseous composition constituting the medicament is formed of a gas mixture containing, in addition, oxygen, nitrogen or their mixtures, in particular air. - The gaseous composition constituting the drug is formed of a binary gas mixture consisting of argon and oxygen for the rest. the gaseous composition constituting the medicament is packaged in a gas bottle having a capacity (water equivalent) of up to 50 liters, typically of the order of 5 to 15 liters. - The gaseous composition constituting the drug is packaged in a gas cylinder in which the gaseous composition is at a pressure less than or equal to 350 bar absolute. - The gaseous composition constituting the drug is packaged in a gas cylinder equipped with a tap or an integrated pressure reducer valve for controlling the flow rate and optionally the pressure of the gas delivered. - The gaseous composition constituting the drug is packaged in a gas cylinder made of steel, aluminum or composite materials. The present invention is therefore based on the use by inhalation of argon gas as an inhalable drug, combined with hypothermia, to prevent or treat any neurological consequence likely to be caused by neonatal hypoxia of ischemic origin, consecutive to Perinatal asphyxia in a newborn.

In fact, argon has protective properties of the brain, as recalled in EP-A-1541156 which proposes using inhaled argon to combat brain neuro-intoxications. The mechanisms of action of argon are, however, still poorly known and could be based on an agonist action of GABAA receptors, in particular the benzodiazepine site, as described by J. Abraini et al., Anesth. Analg., 2003, 96: 746-749. Recently, the argon neuroprotective capacity has been confirmed by Loetscher et al. ; in Critical Care, 2009, 13: R206, doi: 10.1186 / cc8214. Argon has also been shown to be able to protect cochlear cells in isolated culture, that is to say the so-called hair cells derived from the body of rat Corti, as described by Yarin et al., Hear Res 2005, 201: 1-9. These cells are comparable to cerebral neurons, for which other gases, in particular xenon, have been shown to have a neuroprotective effect, as recalled by Ma et al., Br J Anaesth, 2002, vol 98: 739-46. The solution of the invention is therefore based on these properties of argon and then proposes a gaseous drug, that is to say a gaseous composition containing gaseous argon and at least 20% by volume of gaseous argon. Oxygen for rapid use by direct inhalation via a cannula, mask or bell or indirectly as part of an incubator equipped to control the atmosphere of the incubator and ensure the necessary balance between oxygen and argon and to control the drop in body temperature, particularly that of the brain, to achieve the desired hypothermia, simultaneously administering argon gas to the patient. Indeed, in the context of the present invention, it has been demonstrated that an argon-based gas is capable, in combination with hypothermia, of preserving the brain from EHI-induced brain damage in connection with Perinatal asphyxia in the newborn. Perinatal asphyxia results in a lack of oxygen in the infant's brain during childbirth, at the time of birth and / or immediately after birth, causing hypoxic-ischemic encephalopathy or EHI. This pathology concerns 3 to 5 neonates per 1000 live births in developed countries. Furthermore, the invention also relates to a use of argon gas in combination with hypothermia to manufacture an inhalable drug composition according to the invention intended to prevent or treat the secondary neurological consequence (s) related to neonatal hypoxia of origin. ischemic, by perinatal asphyxia, hypothermia being defined by a body temperature lowered by a few degrees but above 30 ° C, typically a body temperature lowered between 32 and 35 to 36 ° C, and maintained for a period of less than 72 hours typically for a period of from 1 hour to 24 hours.

In general, during the treatment, the administration of the gaseous composition to the patient is by inhalation, for example by means of a fan, a nebulizer or spontaneously with pre-conditioned gas bottles, connected to a facial or nasal mask, to nasal goggles, through an intubation tip or directly via an incubator whose atmosphere is controlled. The duration of administration is a function of the evolution of the neurological state, chosen on a case-by-case basis affecting the patient in question, for example the argon may be administered for a duration of administration of a few minutes to a few tens of minutes, even hours, for example less than one hour, at a frequency of up to one to several times a day and over a total duration of treatment of one or more days, weeks. The argon or argon-based gaseous mixture forming the gaseous composition or the inhalable drug according to the present invention is preferably packaged in a bottle of gas under pressure or in liquid form, for example in a bottle of one to several liters ( containing water) and at a pressure of between 2 and 300 bar. Argon or the gas mixture based on argon may be in the form of a "ready-to-use" medicament, for example by premixing with oxygen, or may be mixed on site during its use, especially with oxygen and optionally another gaseous compound, for example nitrogen.

In all cases, argon being administered by inhalation, it is essential that it be mixed with at least 21% oxygen (% vol.) Before inhalation by the newborn patient who, as part of the The invention is that the patient is a hypoxemic newborn who is placed in controlled hypothermia, that is, at a temperature of 36 ° C or less. Moreover, hypothermia can be obtained by various known techniques such as: external cooling, for example using a cooling system (wet sheets) and cold air pulsed so as to obtain a convection cooling, which may be associated with external and / or internal glazing (ie gastric lavage with cold water). External cooling can also be accomplished by immersion in a cold water bath or when localized to the skull with a refrigerated polymerized gel helmet. - An internal cooling by apposition of a cooling system directly into the inferior vena cava within which circulates a cooled liquid that is not in direct contact with the blood, or by extracorporeal circulation and cooling blood out of the body. Note that induction of hypothermia can be achieved by intravenous infusion with cold liquid (<5 ° C). In all cases, the choice of the type of hypothermia to be performed depending on the patient to be treated is a routine therapeutic approach.

Example In order to demonstrate the efficacy of argon in combination with hypothermia in the treatment or prevention of secondary neurological consequences related to neonatal hypoxia of ischemic origin, perinatal asphyxia, the synergistic effect was evaluated. argon associated with hypothermia on an EHI model of neonatal rats that are exposed to each of the treatments. Hypothermia in newborns is achieved by placing the animal in contact with ice. In order to protect the animal against potential burns that could result from direct contact between the skin and the ice, a protective barrier is placed between the animal and the ice; the animal being in a glove, a wet compress or a plastic film and placed on the ice until a body temperature of about 20 ° C. The animals are placed in boxes where the gaseous atmosphere containing 75% of argon and 25% of Oz (% by volume) is regulated, via a semi-closed circuit. The argon of the mixture is replaced by nitrogen for the control group Nitrogen and, moreover, the argon / oxygen mixture is replaced by air for the AIR control group. The results obtained are shown below. In-vivo study in newborn rats Healthy brain Control group AIR Activity level 0 reference Control group NITROGEN + Hypothermia group - Argon group - Hypothermia + Argon group --- 30 A favorable response is indicated by a sign ( -), proof of the decrease of the level of apoptosis, and thus of the cerebral infarction. Conversely, an unfavorable response is represented by a sign (+), signal of an increase of apoptotic activity and thus of cell death.

As can be seen, argon shows a neuroprotective effect against the consequences of HIE, whereas hypothermia alone appears to be less effective. Similarly, argon was found to be more effective than the mixtures administered to the AIR and NITROGEN groups.

On the other hand, in combination argon and hypothermia which act by different mechanisms, namely N-MDA receptors for hypothermia and argon GABAA receptors synergize their actions in order to have a higher activity than the use of hypothermia alone. Indeed, it is in the case of such an argon / hypothermia combination that the decrease in the level of apoptosis and cerebral infarction is the most important. This demonstrates the effectiveness of the combination according to the present invention of inhaled argon gas and hypothermia for preventing or treating a neurological consequence related to neonatal hypoxia of ischemic origin, following perinatal asphyxia in a newborn. born.

Claims (10)

REVENDICATIONS1. An inhalable drug containing argon gas for inhalation use in combination with hypothermia to prevent or treat a neurological consequence related to neonatal hypoxia of ischemic origin following perinatal asphyxia in a neonate. 2. Medicament according to the preceding claim, characterized in that it contains between 15 and 80% by volume of argon (% by volume). 3. Medicament according to one of the preceding claims, characterized in that it contains at least 20% by volume of argon, preferably at least 30% by volume of argon, or it contains less than 75% by volume of 'argon. 4. Medicament according to one of the preceding claims, characterized in that the newborn is a human less than 30 days old. 5. Medicament according to one of the preceding claims, characterized in that the hypothermia is obtained by maintaining the body temperature of the newborn between 30 and 36 ° C, typically between 32 and 35 ° C. 6. Medicament according to one of the preceding claims, characterized in that the body temperature of the newborn between 30 and 36 ° C is maintained for a period of between 1 h and 72 h, preferably at least 4 h. 7. Medicament according to one of the preceding claims, characterized in that it contains exclusively argon, said argon being mixed with oxygen before inhalation by the newborn, preferably at least 21% by volume oxygen. 8. Medicament according to one of claims 1 to 6, characterized in that it further contains oxygen, preferably at least 21% by volume of oxygen. 9. Medicament according to one of claims 1 to 6, characterized in that it further contains an additional compound selected from the group consisting of N20, He, Ne, NO, CO, and N2. 10. Medicament according to one of claims 1 to 6, characterized in that it consists of argon and oxygen .. Medicament according to one of claims 1 to 6 and 8 or 9, characterized in that it consists of argon, nitrogen and oxygen.